When
a drug such as caffeine or aspirin turns out to have a great variety
of protective effects, it's important to understand what it's doing.

Because
aspirin has been abused by pharmaceutical companies that have competing
products to sell, as well as by the original efforts to promote aspirin
itself, people can easily find reasons why they shouldn't take it.

Early
in the 20th century, people were told that fevers were very bad, and
that aspirin should be used whenever there is a fever.

In
the 1980s, there was a big publicity campaign warning parents that giving
aspirin to a child with the flu could cause the potentially deadly Reye
syndrome. Aspirin sales declined sharply, as sales of acetaminophen
(Tylenol, etc.) increased tremendously. But in Australia, a study of
Reye syndrome cases found that six times as many of them had been using
acetaminophen as had used aspirin. (Orlowski, et al., 1987)

Until
the 1950s and 1960s, when new products were being promoted, little was
said about the possibility of stomach ulceration from aspirin. Lately,
there has been more publicity about the damage it can do to the stomach
and intestine, much of it in connection with the sale of the new "COX-2
inhibitors." (These new drugs, rather than protecting the circulatory
system as aspirin does, damage it.) Aspirin rapidly breaks down into
acetic acid and salicylic acid (which is found in many fruits), and
salicylic acid is protective to the stomach and intestine, and other
organs. When aspirin was compared with the other common antiinflammatory
drugs, it was found that the salicylic acid it releases protects against
the damage done by another drug. (Takeuchi, et al, 2001; Ligumsky, et
al., 1985.) Repeated use of aspirin protects the stomach against very
strong irritants. The experiments in which aspirin produces stomach
ulcers are designed to produce ulcers, not to realistically model the
way aspirin is used.

Recently,
the public has been led to believe that drugs are being designed to
fit certain cellular "receptors." The history of the "COX-2
inhibitors" is instructive, in a perverse way. The structures of
DES and other synthetic estrogens were said to relate to "the estrogen
receptor." Making these estrogenic molecules more soluble in water
made them somewhat anti-estrogenic, leading to products such as Tamoxifen.
But some of the molecules in this group were found to be antiinflammatory.
The structure of Celecoxib and other "COX-2 inhibitors" is
remarkably similar to the "designer estrogens." Considering
this, it's a little odd that so few in the U.S. are openly discussing
the possibility that estrogen's function is directly related to inflammation,
and involves the production of many inflammatory mediators, including
COX-2. (See Lerner, et al., 1975; Luo, et al., 2001; Cushman, et al,
2001; Wu, et al., 2000; Herrington, et al., 2001.)

Soot
and smoke contain many chemicals that produce inflammation (Brune, et
al., 1978). In the 1930s, soot was known to be both carcinogenic and
estrogenic, and analysis of its components led to the production of
the early commercial estrogens. Any intelligent person reading the chemical
and biological publications of that time will see how closely associated
cancer, inflammation, and estrogen are.

Soon
after vitamin E was discovered, tocopherol was defined as a brain-protective,
pregnancy protective, male fertility protective, antithrombotic, antiestrogenic
agent. But very soon, the estrogen industry made it impossible to present
ideas that explained vitamin E, progesterone, vitamin A, or thyroid
hormone in terms of the protection they provide against estrogenic substances.
Since the polyunsaturated fats caused the same conditions that were
caused by unopposed estrogen, vitamin E came to be known as an "antioxidant,"
because it reduced their toxicity. (Vitamin E is now known to
suppress COX-2, synergizing with aspirin and opposing estrogen.)

In
1970, when I was beginning to see the ways in which unopposed estrogen
and accumulated polyunsaturated fats interacted with a vitamin E deficiency
during aging and in infertility, I got some prostaglandins to experiment
with, since they are products of the oxidation of linoleic acid. The
prostaglandins are an interesting link between estrogens and inflammation,
in normal physiology as well as in disease.

I
wanted to test their effects on the uterus, especially the sites where
the embryos implant. There was a theory that the electrical charge of
the surface of the uterus was decreased at the implantation sites, to
reduce the repulsion between two negatively charged things. Although
there were regions of lower surface charge along the lining of the uterus,
the charge changed as waves of muscle contraction moved along the uterus,
and the prostaglandins affected the contractions.

To
understand the differences between the different types of prostaglandin,
I tested them on my arm, and those with the most hydroxyl groups produced
regions with an increased negative charge. For comparison, I exposed
another spot to sunlight for an hour, and found that there was a similar
increase in the negative charge in that spot. Apparently the prostaglandins
were causing an injury or excitation, a mild inflammation, in the skin
cells.

A
few years later, aspirin was found to inactivate the enzyme that forms
prostaglandins, by the transfer of the acetyl radical to the enzyme.
This became the orthodox "explanation" for what aspirin does,
though it neglected to explain that salicylic acid (lacking the acetyl
radical) had been widely known in the previous century for its very
useful antiinflammatory actions. The new theory did explain (at least
to the satisfaction of editors of medical magazines) one of aspirin's
effects, but it distracted attention from all the other effects of aspirin
and salicylic acid.

Aspirin
is an antioxidant that protects against lipid peroxidation, but it also
stimulates mitochondrial respiration. It can inhibit abnormal cell division,
but promote normal cell division. It can facilitate learning, while
preventing excitotoxic nerve injury. It reduces clotting, but it can
decrease excessive menstrual bleeding. These, and many other strangely
beneficial effects of aspirin, strongly suggest that it is acting on
very basic biological processes, in a coherent way.

In
explaining aspirin's effects, as in explaining those of estrogen and
progesterone, or polyunsaturated fats and vitamin E, I think we need
concepts of a very broad sort, such as "stability and instability."

The
COX (cyclooxygenase) enzymes, that make prostaglandins, are just one
system among many that are activated by stress. Aromatase, that makes
estrogen, enzymes that make histamine, serotonin and nitric oxide, the
cytokines, and the stress-induced hormones of the pituitary and adrenal
glands, are turned on in difficult situations, and have to be turned
off when the threat has been overcome. The production of energy is the
basis for overcoming all threats, and it has to be conserved in readiness
for future needs.

The
fetus produces saturated fats such as palmitic acid, and the monounsaturated
fat, oleic acid, which can be turned into the Mead acid, ETrA (5,8,11-eicosatrienoic
acid), and its derivatives, which are antiinflammatory, and some of
which act on the "bliss receptor," or the cannibinoid receptor.
In the adult, tissues such as cartilage, which are protected by their
structure or composition from the entry of exogenous fats, contain the
Mead acid despite the presence of linoleic acid in the blood.

At
birth, the baby's mitochondria contain a phospholipid, cardiolipin,
containing palmitic acid, but as the baby eats foods containing polyunsaturated
fatty acids, the palmitic acid in cardiolipin is replaced by the unsaturated
fats. As the cardiolipin becomes more unsaturated, it becomes less stable,
and less able to support the activity of the crucial respiratory enzyme,
cytochrome oxidase.

The
respiratory activity of the mitochondria declines as the polyunsaturated
oils replace palmitic acid, and this change corresponds to the life-long
decline of the person's metabolic rate.

In
old age, a person's life expectancy strongly depends on the amount of
oxygen that can be used. When the mitochondria can't use oxygen vigorously,
cells must depend on inefficient glycolysis for their energy.

Estrogen
activates the glycolytic pathway, while interfering with mitochondrial
respiration. This resembles the aged or stressed metabolism, in which
lactic acid is produced instead of carbon dioxide.

Aspirin
activates both glycolysis and mitochondrial respiration, and this means
that it shifts the mitochondria away from the oxidation of fats, toward
the oxidation of glucose, resulting in the increased production of carbon
dioxide. Its action on the glycolytic enzyme, GAPDH, is the opposite
of estrogen's.

The
shift away from fat oxidation under the influence of aspirin doesn't
lead to an accumulation of free fatty acids in the circulation, since
aspirin inhibits the release of fatty acids from both phospholipids
and triglycerides. Estrogen has the opposite effects, increasing fat
oxidation while increasing the level of circulating free fatty acids,
since it activates lipolysis, as do several other stress-related hormones.

The
polyunsaturated fatty acids, such as linolenic, linoleic, arachidonic,
EPA, and DHA, have many directly toxic, antirespiratory actions, apart
from the production of the prostaglandins or eicosanoids. Just by preventing
the release of these fatty acids, aspirin would have broadly antiinflammatory
effects.

Since
the polyunsaturated fats and prostaglandins stimulate the expression
of aromatase, the enzyme that synthesizes estrogen, aspirin decreases
the production of estrogen. So many of aspirin's effects oppose those
of estrogen, it would be tempting to suggest that its "basic action"
is the suppression of estrogen. But I think it's more likely that both
estrogen and aspirin are acting on some basic processes, in approximately
opposite ways.

Bioelectrical
functions, and the opposition between carbon dioxide and lactic acid,
and the way water is handled in cells, are basic conditions that have
a general or global effect on all of the other more specific biochemical
and physiological processes. Originally, estrogen and progesterone were
each thought to affect only one or a few biochemical events, but it
has turned out that each has a multitude of different biochemical actions,
which are integrated in globally meaningful ways. The salicylic acid
molecule is much smaller and simpler than progesterone, but the range
of its beneficial effects is similar. Because of aspirin's medical antiquity,
there has been no inclination to explain its actions in terms of an
"aspirin receptor," as for valium and the opiates, leaving
its biochemistry, except for the inadequate idea of COX-inhibition,
simply unexplained.

If
we didn't eat linoleic acid and the other so-called "essential
fatty acids," we would produce large amounts of the "Mead
acid," n-9 eicosatrienoic acid, and its derivatives. This acid
in itself is antiinflammatory, and its derivatives have a variety of
antistress actions. The universal toxicity of the polyunsaturated fats
that suppress the Mead fats as they accumulate, and the remarkable vitality
of the animals that live on a diet deficient in the essential fatty
acids, indicate that the Mead fats are important factors in the stability
of our mammalian tissues. This protective lipid system probably interacts
with cellular proteins, modifying the way they bind water and carbon
dioxide and ions, affecting their electrons and their chemical reactivity.

If
salicylic acid and the structurally similar antiinflammatories, local
anesthetics, muscle relaxants, expectorants, and antihistamines, act
as surrogates for the absent Mead acid family, and thereby act as defenses
against all the toxic effects of the unstable fats, it would explain
the breadth and apparent coherence of their usefulness. And at
the same time it explains some of the ways that estrogen goes out of
control, when it exacerbates the toxicity of the accumulated unstable
fats.

The
competition between aspirin and salicylic acid, and other antiinflammatories,
for the active site on the COX enzyme (Rao, et al., 1982), shows that
the structural features of these molecules are in some ways analogous
to those of the polyunsaturated fatty acids. Wherever there are phospholipids,
free fatty acids, fatty acid esters, ethers, etc. (i.e., in mitochondria,
chromosomes, cytoskeleton, collagen networks--essentially everywhere
in and around the cell), the regulatory influence of specific fatty acids--or their surrogates--will be
felt.

Although
it would undoubtedly be best to grow up eating foods with relatively
saturated fats, the use of aspirin preventively and therapeutically
seems very reasonable under the present circumstances, in which, for
example, clean and well ripened fruits are not generally available in
abundance. Preventing blindness, degenerative brain diseases, heart
and lung diseases, and cancer with aspirin should get as much support
as the crazy public health recommendations are now getting from government
and foundations and the medical businesses.

When
people with cancer ask for my recommendations, they usually think I'm
joking when I tell them to use aspirin, and very often they don't take
it, on the basis of what seems to be a very strong cultural prejudice.
Several years ago, a woman whose doctors said it would be impossible
to operate on her extremely painful "inflammatory breast cancer,"
had overnight complete relief of the pain and swelling from taking a
few aspirins. The recognized anti-metastatic effect of aspirin, and
its ability to inhibit the development of new blood vessels that would
support the tumor's growth, make it an appropriate drug to use for pain
control, even if it doesn't shrink the tumor. In studies of many kinds
of tumor, though, it does cause regression, or at least slows tumor
growth. And it protects against many of the systemic consequences of
cancer, including wasting (cachexia), immunosuppression, and strokes.

Opiates
are the standard medical prescription for pain control in cancer, but
they are usually prescribed in inadequate quantities, "to prevent
addiction." Biologically, they are the most inappropriate means
of pain control, since they increase the release of histamine, which
synergizes with the tumor-derived factors to suppress immunity and stimulate
tumor growth.

It
has recently become standard practice in most places to advise a person
who is having a heart attack to immediately chew and swallow an aspirin
tablet.

The
same better-late-than-never philosophy can be applied to Alzheimer's
disease, Parkinson's disease, and other degenerative nerve diseases.
Aspirin protects against several kinds of toxicity, including excitotoxicity
(glutamate), dopamine toxicity, and oxidative free radical toxicity.
Since its effects on the mitochondria are similar to those of thyroid
(T3), using both of them might improve brain energy production more
than just thyroid. (By activating T3, aspirin can sometimes increase
the temperature and pulse rate.) Magnesium, niacinamide, and other nerve
protective substances work together.

In
multiple organ failure, which can be caused by profound shock caused
by trauma, infection, or other stress, aspirin is often helpful, but
carbon dioxide and hypertonic glucose and sodium are more important.

Aspirin,
like progesterone or vitamin E, can improve fertility, by suppressing
a prostaglandin, and improving uterine circulation.

Although
the animal studies that showed stomach damage from aspirin often used
single doses equivalent to 10 or 100 aspirin tablets, the slight irritation
produced by a normal dose of aspirin can be minimized by dissolving
the aspirin in water. The stomach develops a tolerance for aspirin over
a period of a few days, allowing the dose to be increased if necessary.
And both aspirin and salicylic acid can be absorbed through the skin,
so rheumatic problems have been treated by adding the drug to bath water.

The
unsaturated (n-6 and n-3) fats that accumulate in our tissues, instead
of being part of the system for reestablishing order and stability,
tend to amplify the instability that is triggered by excitation, by
estrogen, or by external stresses.

I
think it's important that we don't allow the drug publicists to obscure
the broad importance of substances such as aspirin, vitamin E, progesterone,
and thyroid. For 60 years, a myth that was created to sell estrogen
has harmed both science and the health of many people.

Int
Ophthalmol 1981 May;3(3):173-7. Aspirin effect on cataract formation
in patients with rheumatoid arthritis alone or combined with diabetes.
Cotlier E. "The effects of aspirin on cataract formation may result
from 1) lowering of plasma tryptophan levels and increased excretion
of tryptophan metabolites, 2) inhibition of aldose reductase and sorbitol
formation in the diabetic lens, 3) inhibition of tryptophan or kynurenine
binding to lens protein."

J
Natl Cancer Inst 1998 Mar 18;90(6):455-60. Expression of
cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. Hwang
D, Scollard D, Byrne J, Levine E "Our results suggest that overexpression
of COX may not be unique to colon cancer and may be a feature common
to other epithelial tumors."

J
Cardiovasc Pharmacol 1995 Feb;25(2):273-81. Inhibitory effects
of aspirin on coronary hyperreactivity to
autacoids after arterial balloon injury in miniature pigs. Kuga
T, Ohara Y, Shimokawa H, Ibayashi S, Tomoike H, Takeshita A. "Coronary
vasoconstriction induced by histamine and serotonin were examined angiographically
before, 1 h, 1 week, and 1 month after balloon injury in 29 hypercholesterolemic
miniature pigs." "Hyperconstriction induced by the autacoids
1 h after injury were significantly less in groups B and C than in group
A (p < 0.01). Hyperconstriction induced by autacoids 1 week after
injury were significantly less in group B than in group A (p < 0.01)
and were significantly less in group C than in group A (p < 0.01)
or group B (p < 0.05)."

Neuropharmacology
2000 Apr 27;39(7):1309-18. Mechanisms of the
neuroprotective effect of aspirin after oxygen and glucose deprivation
in rat forebrain slices. Moro MA, De Alba J, Cardenas A, De Cristobal
J, Leza JC, Lizasoain I, Diaz-Guerra MJ, Bosca L, Lorenzo P "Apart
from its preventive actions against stroke due to its antithrombotic
properties, recent data in the literature suggest that high concentrations
of ASA also exert direct neuroprotective effects." "We have
found that ASA inhibits neuronal damage at concentrations lower than
those previously reported (0.1-0.5 mM), and that these effects correlate
with the inhibition of excitatory amino acid release, of NF-kappaB translocation
to the nucleus and iNOS expression caused by ASA." "Our results
also show that the effects of ASA are independent of COX inhibition.
Taken together, our present findings show that ASA is neuroprotective
in an in vitro model of brain ischaemia at doses close to those recommended
for its antithrombotic effects."

Clin
Exp Immunol 1991 Nov;86(2):315-21. Piroxicam,
indomethacin and
aspirin action on a murine fibrosarcoma. Effects on tumour-associated
and peritoneal macrophages. Valdez JC, Perdigon G. "We also studied
the effect on tumour development of three inhibitors of prostaglandin
synthesis: indomethacin, piroxicam and aspirin. Intraperitoneal administration
of these drugs during 8 d was followed by the regression of palpable
tumours. Indomethacin (90 mg/d) induced 45% regression, while with piroxicam
(two 400 mg/d doses and six 200 mg/d doses) and aspirin (1 mg/d) 32%
and 30% regressions, respectively, were observed. The growth rate of
nonregressing tumours, which had reached different volumes by the end
of the treatment, was delayed to a similar extent by the three anti-inflammatory
non-steroidal drugs (NSAID)."

Dermatologica
1978;156(2):89-96. Effect of topical salicylic acid on animal
epidermopoiesis. Weirich EG, Longauer JK, Kirkwood AH. In contrast
to its antihyperplastic effect on pathological proliferation of the
epidermis, salicylic acid promotes epidermopoiesis in the normal guinea
pig skin. After the application of 1% w/w salicylic acid in acetone-ethanol
for 4 weeks, the thickness of the surface epithelium was increased by
40% and that of the deep epithelium by 19%. The mitotic index rose by
17%.

Arch
Exp Veterinarmed 1981;35(3):465-70. [Control of implantation
in rats and sows by peroral administration of prostaglandin
synthetase inhibitors. 2. Effects of prostaglandin F2 alpha,
progesterone/estrone, and acetylsalicylic acid on implantation and various
biochemical parameters of amniotic fluid in the rat] Wollenhaupt
K, Steger H. "The highest number of normally developed (97 per
cent) and the lowest number of degenerated foetuses (three per cent)
were recorded following acetylsalicylic acid treatment, as compared
to the control group (91 and nine per cent)."

Since
the 1970s, aspirin has been thought of as an inhibitor of prostaglandin
synthesis, but that is only part of its effect. Sometimes its effect
is the opposite of the effects of other prostaglandin inhibitors.

It
prevents cancer, and can cause its regression. It inhibits vascular
proliferation. It inhibits interleukin 6 (and other inflammatory
cytokines), which is a factor in heart disease and breast and liver
cancer.

It
protects the brain, and can improve learning. It's an antioxidant, prevents
cataracts, and protects against glycation in diabetes.

It
prevents premature birth and prevents birth defects caused by diabetes,
preeclampsia, and exposure to alcohol. It prevents recurrence of neural
tube defects and protects against many of the
gestational problems associated with lupus.

Although
aspirin protects against uncontrolled cell proliferation, as in cancer
and psoriasis, salicylic acid increases normal cell division in the
skin.

Aspirin
protects against many forms of shock and
stess, and corrects imbalances in the nervous system.

It protects against several
kinds of toxins involved in brain degeneration.

"Aspirin
elevated ATP levels not only in intact cortical neurons but also in
isolated brain mitochondria, an effect concomitant with an increase
in NADH-dependent respiration by brain
submitochondrial particles."